2. Academic Validation
  3. Synthesis, characterization and anti-breast cancer activities of stachydrine derivatives

Synthesis, characterization and anti-breast cancer activities of stachydrine derivatives

  • Eur J Med Chem. 2023 Jul 26;259:115679. doi: 10.1016/j.ejmech.2023.115679.
Huahui Zeng 1,  Duanjie Xu 1,  Yagang Song 1,  Shuo Tian 1,  Jingyi Qiao 1,  Zhanzhan Li 1,  Lingzhou Zhao 2,  Hui Shi 3,  Yueyue Zhou 3,  Shuo Li 4,  Ying Luo 4,  Jiashi Li 4,  Mingsan Miao 5,  Xiangxiang Wu 6
Affiliations

Affiliations

  • 1 Academy of Chinese Medicine Science, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
  • 2 Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
  • 3 Pharmacy College, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
  • 4 Joint Institute of Management and Science University, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
  • 5 Academy of Chinese Medicine Science, Henan University of Chinese Medicine, Zhengzhou, 450046, China. Electronic address: miaomingsan@126.com.
  • 6 Academy of Chinese Medicine Science, Henan University of Chinese Medicine, Zhengzhou, 450046, China. Electronic address: wuxx-415@hactcm.edu.cn.
PMID: 37517203 DOI: 10.1016/j.ejmech.2023.115679
Abstract

Stachydrine is a hydrophilic quaternary amine salt with good antitumor effect, but its application is limited due to its rapid metabolism and low bioavailability. We synthesized and evaluated nine prodrugs of stachydrine, which showed suitable hydrophobicity (CLogP: -2.58-4.78, vs SS-0: -3.32) and better in vitro Anticancer activity (IC50: 0.34 μM-14.03 mM, vs SS-0: 38.97 mM-147.19 mM) in comparison with stachydrine. Among them, SS-12, SS-16 and SS-18 are the most effective compounds against 4T1 cells, and the IC50 is 2.15-24.14 μM. Especially, compared with stachydrine, SS-12 significantly blocked the cell cycle in the G0/G1 phase, reduced the mitochondrial membrane potential, and induced the Apoptosis of 4T1 cells through mitochondria pathway, which increased the expressions of Bax and cleaved Caspase-3 protein, decrease the expression of Bcl-2. The pharmacokinetics of SS-12 showed a rational bioavailability (79.6%), and a longer retention time (T1/2 = 7.62 h) than that of stachydrine (T1/2 ≈ 1.16 h) in rats. Compared with stachydrine, SS-12 significantly enhanced the Anticancer efficacy (56.32% of tumor-inhibition rates, vs SS-0: 3.89%), meanwhile, ameliorated the tumor-induced organ damage in mice. Therefore, SS-12 may be a promising prodrug of stachydrine against breast Cancer.

Keywords

Bioavailability; Breast cancer; Derivative; Drug design; Stachydrine.

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